Inflammation of the large intestine, such as colitis, is known to increase the risk of colorectal cancer in human. The colitis induced by dextran sodium sulfite (DSS) has been shown to promote carcinogen- and genetic-induced colon tumorigenesis in rodent models. In a CYP1A-humanized (hCYP1A) mouse colon cancer model that we developed to study dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), DSS-induced colitis was required for colon tumor development after the PhIP treatment. Nevertheless, the mechanism for DSS-induced colitis to promote carcinogenesis is not clear. To uncover the key cancer promotion factor induced by colitis is important in understanding the mechanism of colon cancer development. By investigating the gene expression profiles of PhIP/DSS-induced colon tumors and normal colon epithelium, we found that cytokine IL11 was significantly upregulated in all tumors. The elevated levels of IL11 are also found in the human colon cancer genomic data available in The Cancer Genome Atlas (TCGA), suggesting an important role of IL11 in human colon cancer. Consistently, the activation/phosphorylation of STAT3, a key downstream factor of IL11 signaling, was also positively identified in tumors but not the normal adjacent tissues. To investigate the role of IL11 signaling, we generated hCYP1A:IL11Rα1-/- mice for investigating the role of IL11 signaling in PhIP/DSS-induced carcinogenesis by crossing the IL11Rα1-/- mice with hCYP1A mice. These mice are infertile as the phenotype reported previously for the IL11Rα1 knockout mice, and need to be maintained through the breeding by the heterozygous. The experimental mice were maintained on the AIN93M diet. We found that the tumor incidence was reduced by 51.0% in hCYP1A:IL11Rα1+/- mice and 80.0% in hCYP1A:IL11Rα1-/- mice, suggesting that IL11 signaling plays critical roles in PhIP/DSS-induced colon carcinogenesis. By immunohistochemical staining for pSTAT3, we found the pSTAT3 staining in the colitis epithelial tissues induced by the DSS treatment in both heterozygous and homozygous mice were significantly reduced; whereas the tissues from the wildtype mice displayed strong positive staining in the nucleus. IL11 signaling could be a potential therapeutic target for colon cancer prevention. (supported by the John L. Colaizzi Chair Endowment Fund and GI Pilot Study from Rutgers Cancer Institute of New Jersey Cancer Center Support Grant P30CA072720)

Citation Format: Hong Wang, David Wang, Yuhai Sun, Xu Yang, Chung S. Yang. IL11 promotes the PhIP/DSS-induced colon carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3433.